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CMV induces rapid NK cell maturation in HSCT recipients
Immunology Letters 155 (2013) 11–13
Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Review
CMV induces rapid NK cell maturation in HSCT recipients Mariella Della Chiesa, Letizia Muccio, Alessandro Moretta ∗ DI.ME.S., Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
a r t i c l e
i n f o
Article history: Available online 26 September 2013 Keywords: HCMV infection NKG2C KIR Hematopoietic stem cell transplantation NK cell maturation
a b s t r a c t Natural killer (NK) cells are important effectors of innate immune responses against virally infected cells and tumors. Since NK cells are the first lymphocyte population to recover after hematopoietic stem cell transplantation, they are thought to play a crucial role in early immunity after transplantation against infections. In individuals experiencing HCMV reactivation after transplantation, NK cells rapidly achieved a fully differentiated stage of maturation, characterized by a KIR+ NKG2A− NKG2C+ CD57+ p75/AIRM1− surface phenotype. Patients who never had HCMV reactivation maintained an immature NK phenotype for a long time. Thus, HCMV reactivation, by providing stimulatory signals to maturing NK cells, could be beneficial rather than detrimental. HCMV infection has been reported to induce a persistent reconfiguration of the NK-cell compartment not only in immunocompromised patients but also in healthy individuals, the hallmark of which is the expansion of an NK-cell subset displaying high surface levels of the CD94/NKG2C receptor. Moreover, as suggested by studies in mice, NK cells developing after CMV reactivation could contain “memory” or “long-lived” NK cells that could be exploited for therapeutic purposes. © 2013 Elsevier B.V. All rights reserved.
1. Introduction NK cells are lymphocytes that participate in the early phases of innate immune responses and play an important role in the defense against viral infections and in tumor surveillance [1–5]. They are also involved in shaping adaptive immune responses through their production of various cytokines and chemokines including IFN-␥, TNF-␣, MIP-1␣, MIP-1 and RANTES [6–8]. Under normal homeostatic conditions, the function of human NK-cell is tightly regulated by a balance of activating and inhibitory signals generated upon engagement of different surface receptors. Among the inhibitory receptors a crucial role is mediated by the inhibitory killer cell immunoglobulin-like receptors (KIRs) that recognize allelic epitopes present on certain class I human leukocyte antigens (HLAs) [9–12] and the C-type lectin-like receptor NKG2A, which recognizes nonclassical, HLA-E molecules [13,14]. When HLA class I is down-regulated following tumor transformation or viral infection, cells become susceptible to NK-cell lysis because of the lack of ligands for the inhibitory receptors, a phenomenon known as “missing-self” [15].
Abbreviations: (H)CMV, (human) cytomegalovirus; HSCT, hematopoietic stem cell transplantation. ∗ Corresponding author at: Dipartimento di Medicina Sperimentale, Sezione di Istologia, Via G.B. Marsano 10, 16132 Genova, Italy. Tel.: +39 010 3537868; fax: +39 010 3537576. E-mail address: [email protected] (A. Moretta). 0165-2478/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.imlet.2013.09.020
Activating signals are mediated by a series of receptor families, including activating KIR [16–18], NKG2C [13,19] (13,20), the natural cytotoxicity receptors (NKp30, NKp44, and NKp46) [20,21], NKG2D [22,23], CD226 [24], CD16 [25] and CD244 [26]. The ligands recognized by these receptors are either represented by HLA class I (activating KIR and NKG2C) or by molecules that are induced/upregulated at the cell surface of cells in response to stress/infection (NCR, NKG2D, CD226) [27]. 2. NK cells and CMV infection Human CMV is a betaherpesvirus replicating in different cell types, which is commonly transmitted by secretions [28]. Most humans are infected with CMV (50–100% depending on geographical location and socioeconomic factors), and remain infected for life [29]. This viral infection generally follows a subclinical course in immunocompetent hosts and remains latent, undergoing occasional reactivation. The control of viral replication is due to the combined action of NK and T cells, together with specific Ig production. The primary infection is often acquired in childhood but is normally subclinical or mild [28]. Viral release in milk may cause an early postnatal infection, which may become symptomatic particularly in premature infants. In adults HCMV infection/reactivation becomes an important cause of morbidity in primary or acquired immunodeficiencies and immunosuppressed patients particularly in transplant recipients. It is well known that HCMV infections, by different mechanisms, can inhibit the expression of MHC class I molecules in infected cells
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M. Della Chiesa et al. / Immunology Letters 155 (2013) 11–13
Fig. 1. CMV accelerates NK cell maturation after HSCT. Schematic representation of NK cell maturation from CD34+ HSC in recipients reactivating CMV. NK cell development is rapidly driven toward a mature stage of differentiation characterized by a KIR+ NKG2A− NKG2C+ CD57+ Siglec-7− surface phenotype.
[30]. Indeed, by this mechanism, several proteins encoded by this virus including US2, US3, US6, US10, US11 have been shown to interfere with antigen recognition by cytolytic CD8+ T cells. However this strategy to evade T cell-mediated immunosurveillance may also result in lowering of the threshold for NK-cell activation against infected cells. The increased susceptibility to NK cells would be secondary to the impaired engagement of their inhibitory NKRs specific for HLA-I molecules [30]. Along this line a primary role for NK cells in defense against CMV was suggested by studies both in mice and in humans. For example it was demonstrated that during mouse cytomegalovirus (MCMV) infection, a population of Ly49H+ NK cells expands and is responsible for disease clearance through the induction of a “memory-like NK cell response” [31]. Similarly human cytomegalovirus (HCMV) has been reported to induce in healthy individuals as well as in patients with different pathological conditions a persistent reconfiguration of the NK-cell compartment, the hallmark of which is the expansion of an NK-cell subset displaying high surface levels of the CD94/NKG2C receptor specific for HLA-E [32,33,34]. In mice, NK cells expressing the activating receptor Ly49H persist in high numbers after CMV infection, and this response is driven by the interaction of Ly49H with the viral protein m157 [35]. In humans, NK cells expressing the activating receptor NKG2C preferentially expand after coculture with CMV-infected fibroblasts and are highly enriched in seropositive individuals [32,36]. On the other hand in CMV-seronegative people, the frequency of NK cells expressing NKG2C is low [32]. Remarkably this expanded NKG2C+ NK cell subset found in CMV+ individuals is also characterized by a mature phenotype, mostly KIR+ NKG2A− . Thus, the emerging concept is that CMV infection is capable of shaping the human NK cell receptor repertoire, favoring the preferential expansion of memory-like NKG2C+ KIR+ NK cells and their persistence over time. Interestingly although an expansion of NKG2C+ NK cells was also observed after infections with other viruses including HIV [37,38], Hantavirus [39], Chikungunya [40], HBV and HCV [41], it is conceivable that the CMV co-infection/reactivation that often occurs in chronically infected subjects, may be responsible for the memory-like NK cell phenotype found in these patients. Together these observations suggested that the NKG2C receptor could play a crucial role in the NK cell expansion and/or maturation driven by HCMV infection. However it is still unclear which are the signals provided directly or indirectly by CMV that are able to drive the expansion/maturation of NKG2C+ NK cells and whether these cells could actually contribute to the control of CMV infection through a mechanism similar to that observed for Ly49H+ NK cells during mouse CMV infection [35]. In this context, a role for NKG2C+ NK cells has been proposed in the resolution of HCMV infection in a T-cell deficient patient [42]. However, different from the Ly49H receptor that is specific for the CMV-encoded viral protein m157, no direct evidence for the specificity of NKG2C for HLA-E molecules
loaded with viral peptides, or for an unknown ligand of either host or viral origin expressed by CMV-infected cells could be obtained so far. Along this line it is also unknown why CMV infection is leading to the dramatic down-regulation of Siglec-7 in CD56 dull (mature) NK cells [43,44]. This feature, together with NKG2C up-regulation, represents indeed the most typical marker of NK cell expansions promoted by CMV infection. 3. CMV accelerates NK cell maturation following HSCT Regarding the CMV imprinting in NK cells from patients following HSCT two recent studies demonstrated that during the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56dim NK cells expressing the NKG2C+ NKG2A− KIR+ Siglec-7− CD57+ signature [43,45,46] (Fig. 1). Importantly, increased frequencies of NK cells expressing these phenotypic features persisted and continued to increase after one year from HSCT in recipients who reactivated CMV, whereas they remained at low frequency in HSCT recipients without CMV reactivation. These results demonstrated that CMV can dramatically accelerate the process of NK cell maturation after HSCT. Importantly most of these NK cells displayed full competence in terms of cytolytic activity and cytokine production. Notably, in the case of KIR-mismatched haplo-HSCT, this phenomenon may be of particular benefit because it results in rapid expansion of alloreactive NK cells that are typically characterized by the KIR+ NKG2A− phenotype [47,48]. In this context, a recent study reported a correlation between early HCMV reactivation and reduction of leukemia relapse after allogenic HSCT in adult patients [49]. Thus, HCMVinduced NK cell populations with a memory-like surface phenotype may contribute not only to the control of virus infection but also to the protection from leukemia relapses after HSCT. Conflict of interest disclosure A.M. is a founder and shareholder of Innate-Pharma (Marseille, France). The remaining authors declare no conflicts of interest. Acknowledgments Supported by Grants awarded by Associazione Italiana Ricerca sul Cancro: IG project n. 10643 (A.M) and Special Project 5x1000 n. 9962 (A.M.); Ministero dell’Istruzione, dell’Università e della Ricerca (M.I.U.R.); and Progetto Ricerca Ateneo 2012 (M.D.C.). References [1] Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science 2011;331:44–9.
M. Della Chiesa et al. / Immunology Letters 155 (2013) 11–13 [2] Caligiuri MA. Human natural killer cells. Blood 2008;112:461–9. [3] Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L. What is a natural killer cell? Nat Immunol 2002;3:6–8. [4] Lanier LL. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 2008;8:259–68. [5] Yokoyama WM, Kim S, French AR. The dynamic life of natural killer cells. Annu Rev Immunol 2004;22:405–29. [6] Robertson MJ. Role of chemokines in the biology of natural killer cells. J Leukoc Biol 2002;71:173–83. [7] Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002;2:957–64. [8] Agaugue S, Marcenaro E, Ferranti B, Moretta L, Moretta A. Human natural killer cells exposed to IL-2, IL-12 IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells. Blood 2008;112:1776–83. [9] Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC, et al. Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol 1996;14:619–48. [10] Lanier LL. NK cell receptors. Annu Rev Immunol 1998;16:359–93. [11] Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002;20:217–51. [12] Long EO, Burshtyn DN, Clark WP, Peruzzi M, Rajagopalan S, Rojo S, et al. Killer cell inhibitory receptors: diversity, specificity, and function. Immunol Rev 1997;155:135–44. [13] Braud VM, Allan DS, O’Callaghan CA, Soderstrom K, D’Andrea A, Ogg GS, et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1998;391:795–9. [14] Lopez-Botet M, Perez-Villar JJ, Carretero M, Rodriguez A, Melero I, Bellon T, et al. Structure and function of the CD94 C-type lectin receptor complex involved in recognition of HLA class I molecules. Immunol Rev 1997;155:165–74. [15] Ljunggren HG, Karre K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 1990;11:237–44. [16] Moretta A, Sivori S, Vitale M, Pende D, Morelli L, Augugliaro R, et al. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J Exp Med 1995;182:875–84. [17] Bottino C, Sivori S, Vitale M, Cantoni C, Falco M, Pende D, et al. A novel surface molecule homologous to the p58/p50 family of receptors is selectively expressed on a subset of human natural killer cells and induces both triggering of cell functions and proliferation. Eur J Immunol 1996;26:1816–24. [18] Della Chiesa M, Romeo E, Falco M, Balsamo M, Augugliaro R, Moretta L, et al. Evidence that the KIR2DS5 gene codes for a surface receptor triggering natural killer cell function. Eur J Immunol 2008;38:2284–9. [19] Lopez-Botet M, Llano M, Navarro F, Bellon T. NK cell recognition of non-classical HLA class I molecules. Semin Immunol 2000;12:109–19. [20] Moretta A, Biassoni R, Bottino C, Mingari MC, Moretta L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol Today 2000;21:228–34. [21] Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001;19:197–223. [22] Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003;3:781–90. [23] Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999;285:727–9. [24] Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 1996;4:573–81. [25] Perussia B, Trinchieri G, Jackson A, Warner NL, Faust J, Rumpold H, et al. The Fc receptor for IgG on human natural killer cells: phenotypic, functional, and comparative studies with monoclonal antibodies. J Immunol 1984;133:180–9. [26] Moretta A, Bottino C, Tripodi G, Vitale M, Pende D, Morelli L, et al. Novel surface molecules involved in human NK cell activation and triggering of the lytic machinery. Int J Cancer Suppl 1992;7:6–10. [27] Bottino C, Castriconi R, Moretta L, Moretta A. Cellular ligands of activating NK receptors. Trends Immunol 2005;26:221–6. [28] Ho M. Epidemiology of cytomegalovirus infections. Rev Infect Dis 1990;12(Suppl. 7):S701–10.
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[29] Dowd JB, Aiello AE, Alley DE. Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III. Epidemiol Infect 2009;137:58–65. [30] Tortorella D, Gewurz BE, Furman MH, Schust DJ, Ploegh HL. Viral subversion of the immune system. Annu Rev Immunol 2000;18:861–926. [31] Sun JC, Lopez-Verges S, Kim CC, DeRisi JL, Lanier LL. NK cells and immune “memory”. J Immunol 2011;186:1891–7. [32] Guma M, Angulo A, Vilches C, Gomez-Lozano N, Malats N, Lopez-Botet M. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 2004;104:3664–71. [33] Muntasell A, Vilches C, Angulo A, Lopez-Botet M. Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host–pathogen interaction. Eur J Immunol 2013;43:1133–41. [34] Malmberg KJ, Beziat V, Ljunggren HG. Spotlight on NKG2C and the human NKcell response to CMV infection. Eur J Immunol 2012;42:3141–5. [35] Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature 2009;457:557–61. [36] Guma M, Budt M, Saez A, Brckalo T, Hengel H, Angulo A, et al. Expansion of CD94/NKG2C + NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 2006;107:3624–31. [37] Guma M, Cabrera C, Erkizia I, Bofill M, Clotet B, Ruiz L, et al. Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1-positive patients. J Infect Dis 2006;194:38–41. [38] Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, et al. Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection. AIDS 2010;24:27–34. [39] Bjorkstrom NK, Lindgren T, Stoltz M, Fauriat C, Braun M, Evander M, et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med 2011;208:13–21. [40] Petitdemange C, Becquart P, Wauquier N, Beziat V, Debre P, Leroy EM, et al. Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog 2011;7:e1002268. [41] Beziat V, Dalgard O, Asselah T, Halfon P, Bedossa P, Boudifa A, et al. CMV drives clonal expansion of NKG2C + NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur J Immunol 2012;42:447–57. [42] Kuijpers TW, Baars PA, Dantin C, van den Burg M, van Lier RA, Roosnek E, et al. Human NK cells can control CMV infection in the absence of T cells. Blood 2008;112:914–5. [43] Della Chiesa M, Falco M, Podesta M, Locatelli F, Moretta L, Frassoni F, et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood 2012;119:399–410. [44] Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, et al. The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer-cell subsets associated with high levels of HIV-1 viremia. Blood 2009;114:3822–30. [45] Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo X, et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C + natural killer cells with potent function. Blood 2011;119:2665–74. [46] Montaldo E, Del Zotto G, Della Chiesa M, Mingari MC, Moretta A, De Maria A. Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. Cytometry A 2013, http://dx.doi.org/10.1002/cyto.a.22302. [47] Ruggeri L, Aversa F, Martelli MF, Velardi A. Allogeneic hematopoietic transplantation and natural killer cell recognition of missing self. Immunol Rev 2006;214:202–18. [48] Moretta L, Locatelli F, Pende D, Marcenaro E, Mingari MC, Moretta A. Killer Ig-like receptor-mediated control of natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation. Blood 2011;117:764–71. [49] Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, et al. Early human cytomegalovirus replication after transplant is associated with a decreased relapse-risk: evidence for a putative virus-versus-leukemia effect AML patients. Blood 2011;118:1402–12.
Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Review
CMV induces rapid NK cell maturation in HSCT recipients Mariella Della Chiesa, Letizia Muccio, Alessandro Moretta ∗ DI.ME.S., Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
a r t i c l e
i n f o
Article history: Available online 26 September 2013 Keywords: HCMV infection NKG2C KIR Hematopoietic stem cell transplantation NK cell maturation
a b s t r a c t Natural killer (NK) cells are important effectors of innate immune responses against virally infected cells and tumors. Since NK cells are the first lymphocyte population to recover after hematopoietic stem cell transplantation, they are thought to play a crucial role in early immunity after transplantation against infections. In individuals experiencing HCMV reactivation after transplantation, NK cells rapidly achieved a fully differentiated stage of maturation, characterized by a KIR+ NKG2A− NKG2C+ CD57+ p75/AIRM1− surface phenotype. Patients who never had HCMV reactivation maintained an immature NK phenotype for a long time. Thus, HCMV reactivation, by providing stimulatory signals to maturing NK cells, could be beneficial rather than detrimental. HCMV infection has been reported to induce a persistent reconfiguration of the NK-cell compartment not only in immunocompromised patients but also in healthy individuals, the hallmark of which is the expansion of an NK-cell subset displaying high surface levels of the CD94/NKG2C receptor. Moreover, as suggested by studies in mice, NK cells developing after CMV reactivation could contain “memory” or “long-lived” NK cells that could be exploited for therapeutic purposes. © 2013 Elsevier B.V. All rights reserved.
1. Introduction NK cells are lymphocytes that participate in the early phases of innate immune responses and play an important role in the defense against viral infections and in tumor surveillance [1–5]. They are also involved in shaping adaptive immune responses through their production of various cytokines and chemokines including IFN-␥, TNF-␣, MIP-1␣, MIP-1 and RANTES [6–8]. Under normal homeostatic conditions, the function of human NK-cell is tightly regulated by a balance of activating and inhibitory signals generated upon engagement of different surface receptors. Among the inhibitory receptors a crucial role is mediated by the inhibitory killer cell immunoglobulin-like receptors (KIRs) that recognize allelic epitopes present on certain class I human leukocyte antigens (HLAs) [9–12] and the C-type lectin-like receptor NKG2A, which recognizes nonclassical, HLA-E molecules [13,14]. When HLA class I is down-regulated following tumor transformation or viral infection, cells become susceptible to NK-cell lysis because of the lack of ligands for the inhibitory receptors, a phenomenon known as “missing-self” [15].
Abbreviations: (H)CMV, (human) cytomegalovirus; HSCT, hematopoietic stem cell transplantation. ∗ Corresponding author at: Dipartimento di Medicina Sperimentale, Sezione di Istologia, Via G.B. Marsano 10, 16132 Genova, Italy. Tel.: +39 010 3537868; fax: +39 010 3537576. E-mail address: [email protected] (A. Moretta). 0165-2478/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.imlet.2013.09.020
Activating signals are mediated by a series of receptor families, including activating KIR [16–18], NKG2C [13,19] (13,20), the natural cytotoxicity receptors (NKp30, NKp44, and NKp46) [20,21], NKG2D [22,23], CD226 [24], CD16 [25] and CD244 [26]. The ligands recognized by these receptors are either represented by HLA class I (activating KIR and NKG2C) or by molecules that are induced/upregulated at the cell surface of cells in response to stress/infection (NCR, NKG2D, CD226) [27]. 2. NK cells and CMV infection Human CMV is a betaherpesvirus replicating in different cell types, which is commonly transmitted by secretions [28]. Most humans are infected with CMV (50–100% depending on geographical location and socioeconomic factors), and remain infected for life [29]. This viral infection generally follows a subclinical course in immunocompetent hosts and remains latent, undergoing occasional reactivation. The control of viral replication is due to the combined action of NK and T cells, together with specific Ig production. The primary infection is often acquired in childhood but is normally subclinical or mild [28]. Viral release in milk may cause an early postnatal infection, which may become symptomatic particularly in premature infants. In adults HCMV infection/reactivation becomes an important cause of morbidity in primary or acquired immunodeficiencies and immunosuppressed patients particularly in transplant recipients. It is well known that HCMV infections, by different mechanisms, can inhibit the expression of MHC class I molecules in infected cells
12
M. Della Chiesa et al. / Immunology Letters 155 (2013) 11–13
Fig. 1. CMV accelerates NK cell maturation after HSCT. Schematic representation of NK cell maturation from CD34+ HSC in recipients reactivating CMV. NK cell development is rapidly driven toward a mature stage of differentiation characterized by a KIR+ NKG2A− NKG2C+ CD57+ Siglec-7− surface phenotype.
[30]. Indeed, by this mechanism, several proteins encoded by this virus including US2, US3, US6, US10, US11 have been shown to interfere with antigen recognition by cytolytic CD8+ T cells. However this strategy to evade T cell-mediated immunosurveillance may also result in lowering of the threshold for NK-cell activation against infected cells. The increased susceptibility to NK cells would be secondary to the impaired engagement of their inhibitory NKRs specific for HLA-I molecules [30]. Along this line a primary role for NK cells in defense against CMV was suggested by studies both in mice and in humans. For example it was demonstrated that during mouse cytomegalovirus (MCMV) infection, a population of Ly49H+ NK cells expands and is responsible for disease clearance through the induction of a “memory-like NK cell response” [31]. Similarly human cytomegalovirus (HCMV) has been reported to induce in healthy individuals as well as in patients with different pathological conditions a persistent reconfiguration of the NK-cell compartment, the hallmark of which is the expansion of an NK-cell subset displaying high surface levels of the CD94/NKG2C receptor specific for HLA-E [32,33,34]. In mice, NK cells expressing the activating receptor Ly49H persist in high numbers after CMV infection, and this response is driven by the interaction of Ly49H with the viral protein m157 [35]. In humans, NK cells expressing the activating receptor NKG2C preferentially expand after coculture with CMV-infected fibroblasts and are highly enriched in seropositive individuals [32,36]. On the other hand in CMV-seronegative people, the frequency of NK cells expressing NKG2C is low [32]. Remarkably this expanded NKG2C+ NK cell subset found in CMV+ individuals is also characterized by a mature phenotype, mostly KIR+ NKG2A− . Thus, the emerging concept is that CMV infection is capable of shaping the human NK cell receptor repertoire, favoring the preferential expansion of memory-like NKG2C+ KIR+ NK cells and their persistence over time. Interestingly although an expansion of NKG2C+ NK cells was also observed after infections with other viruses including HIV [37,38], Hantavirus [39], Chikungunya [40], HBV and HCV [41], it is conceivable that the CMV co-infection/reactivation that often occurs in chronically infected subjects, may be responsible for the memory-like NK cell phenotype found in these patients. Together these observations suggested that the NKG2C receptor could play a crucial role in the NK cell expansion and/or maturation driven by HCMV infection. However it is still unclear which are the signals provided directly or indirectly by CMV that are able to drive the expansion/maturation of NKG2C+ NK cells and whether these cells could actually contribute to the control of CMV infection through a mechanism similar to that observed for Ly49H+ NK cells during mouse CMV infection [35]. In this context, a role for NKG2C+ NK cells has been proposed in the resolution of HCMV infection in a T-cell deficient patient [42]. However, different from the Ly49H receptor that is specific for the CMV-encoded viral protein m157, no direct evidence for the specificity of NKG2C for HLA-E molecules
loaded with viral peptides, or for an unknown ligand of either host or viral origin expressed by CMV-infected cells could be obtained so far. Along this line it is also unknown why CMV infection is leading to the dramatic down-regulation of Siglec-7 in CD56 dull (mature) NK cells [43,44]. This feature, together with NKG2C up-regulation, represents indeed the most typical marker of NK cell expansions promoted by CMV infection. 3. CMV accelerates NK cell maturation following HSCT Regarding the CMV imprinting in NK cells from patients following HSCT two recent studies demonstrated that during the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56dim NK cells expressing the NKG2C+ NKG2A− KIR+ Siglec-7− CD57+ signature [43,45,46] (Fig. 1). Importantly, increased frequencies of NK cells expressing these phenotypic features persisted and continued to increase after one year from HSCT in recipients who reactivated CMV, whereas they remained at low frequency in HSCT recipients without CMV reactivation. These results demonstrated that CMV can dramatically accelerate the process of NK cell maturation after HSCT. Importantly most of these NK cells displayed full competence in terms of cytolytic activity and cytokine production. Notably, in the case of KIR-mismatched haplo-HSCT, this phenomenon may be of particular benefit because it results in rapid expansion of alloreactive NK cells that are typically characterized by the KIR+ NKG2A− phenotype [47,48]. In this context, a recent study reported a correlation between early HCMV reactivation and reduction of leukemia relapse after allogenic HSCT in adult patients [49]. Thus, HCMVinduced NK cell populations with a memory-like surface phenotype may contribute not only to the control of virus infection but also to the protection from leukemia relapses after HSCT. Conflict of interest disclosure A.M. is a founder and shareholder of Innate-Pharma (Marseille, France). The remaining authors declare no conflicts of interest. Acknowledgments Supported by Grants awarded by Associazione Italiana Ricerca sul Cancro: IG project n. 10643 (A.M) and Special Project 5x1000 n. 9962 (A.M.); Ministero dell’Istruzione, dell’Università e della Ricerca (M.I.U.R.); and Progetto Ricerca Ateneo 2012 (M.D.C.). References [1] Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science 2011;331:44–9.
M. Della Chiesa et al. / Immunology Letters 155 (2013) 11–13 [2] Caligiuri MA. Human natural killer cells. Blood 2008;112:461–9. [3] Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L. What is a natural killer cell? Nat Immunol 2002;3:6–8. [4] Lanier LL. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 2008;8:259–68. [5] Yokoyama WM, Kim S, French AR. The dynamic life of natural killer cells. Annu Rev Immunol 2004;22:405–29. [6] Robertson MJ. Role of chemokines in the biology of natural killer cells. J Leukoc Biol 2002;71:173–83. [7] Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002;2:957–64. [8] Agaugue S, Marcenaro E, Ferranti B, Moretta L, Moretta A. Human natural killer cells exposed to IL-2, IL-12 IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells. Blood 2008;112:1776–83. [9] Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC, et al. Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol 1996;14:619–48. [10] Lanier LL. NK cell receptors. Annu Rev Immunol 1998;16:359–93. [11] Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002;20:217–51. [12] Long EO, Burshtyn DN, Clark WP, Peruzzi M, Rajagopalan S, Rojo S, et al. Killer cell inhibitory receptors: diversity, specificity, and function. Immunol Rev 1997;155:135–44. [13] Braud VM, Allan DS, O’Callaghan CA, Soderstrom K, D’Andrea A, Ogg GS, et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1998;391:795–9. [14] Lopez-Botet M, Perez-Villar JJ, Carretero M, Rodriguez A, Melero I, Bellon T, et al. Structure and function of the CD94 C-type lectin receptor complex involved in recognition of HLA class I molecules. Immunol Rev 1997;155:165–74. [15] Ljunggren HG, Karre K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 1990;11:237–44. [16] Moretta A, Sivori S, Vitale M, Pende D, Morelli L, Augugliaro R, et al. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J Exp Med 1995;182:875–84. [17] Bottino C, Sivori S, Vitale M, Cantoni C, Falco M, Pende D, et al. A novel surface molecule homologous to the p58/p50 family of receptors is selectively expressed on a subset of human natural killer cells and induces both triggering of cell functions and proliferation. Eur J Immunol 1996;26:1816–24. [18] Della Chiesa M, Romeo E, Falco M, Balsamo M, Augugliaro R, Moretta L, et al. Evidence that the KIR2DS5 gene codes for a surface receptor triggering natural killer cell function. Eur J Immunol 2008;38:2284–9. [19] Lopez-Botet M, Llano M, Navarro F, Bellon T. NK cell recognition of non-classical HLA class I molecules. Semin Immunol 2000;12:109–19. [20] Moretta A, Biassoni R, Bottino C, Mingari MC, Moretta L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol Today 2000;21:228–34. [21] Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001;19:197–223. [22] Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003;3:781–90. [23] Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999;285:727–9. [24] Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 1996;4:573–81. [25] Perussia B, Trinchieri G, Jackson A, Warner NL, Faust J, Rumpold H, et al. The Fc receptor for IgG on human natural killer cells: phenotypic, functional, and comparative studies with monoclonal antibodies. J Immunol 1984;133:180–9. [26] Moretta A, Bottino C, Tripodi G, Vitale M, Pende D, Morelli L, et al. Novel surface molecules involved in human NK cell activation and triggering of the lytic machinery. Int J Cancer Suppl 1992;7:6–10. [27] Bottino C, Castriconi R, Moretta L, Moretta A. Cellular ligands of activating NK receptors. Trends Immunol 2005;26:221–6. [28] Ho M. Epidemiology of cytomegalovirus infections. Rev Infect Dis 1990;12(Suppl. 7):S701–10.
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[29] Dowd JB, Aiello AE, Alley DE. Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III. Epidemiol Infect 2009;137:58–65. [30] Tortorella D, Gewurz BE, Furman MH, Schust DJ, Ploegh HL. Viral subversion of the immune system. Annu Rev Immunol 2000;18:861–926. [31] Sun JC, Lopez-Verges S, Kim CC, DeRisi JL, Lanier LL. NK cells and immune “memory”. J Immunol 2011;186:1891–7. [32] Guma M, Angulo A, Vilches C, Gomez-Lozano N, Malats N, Lopez-Botet M. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 2004;104:3664–71. [33] Muntasell A, Vilches C, Angulo A, Lopez-Botet M. Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host–pathogen interaction. Eur J Immunol 2013;43:1133–41. [34] Malmberg KJ, Beziat V, Ljunggren HG. Spotlight on NKG2C and the human NKcell response to CMV infection. Eur J Immunol 2012;42:3141–5. [35] Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature 2009;457:557–61. [36] Guma M, Budt M, Saez A, Brckalo T, Hengel H, Angulo A, et al. Expansion of CD94/NKG2C + NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 2006;107:3624–31. [37] Guma M, Cabrera C, Erkizia I, Bofill M, Clotet B, Ruiz L, et al. Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1-positive patients. J Infect Dis 2006;194:38–41. [38] Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, et al. Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection. AIDS 2010;24:27–34. [39] Bjorkstrom NK, Lindgren T, Stoltz M, Fauriat C, Braun M, Evander M, et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med 2011;208:13–21. [40] Petitdemange C, Becquart P, Wauquier N, Beziat V, Debre P, Leroy EM, et al. Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog 2011;7:e1002268. [41] Beziat V, Dalgard O, Asselah T, Halfon P, Bedossa P, Boudifa A, et al. CMV drives clonal expansion of NKG2C + NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur J Immunol 2012;42:447–57. [42] Kuijpers TW, Baars PA, Dantin C, van den Burg M, van Lier RA, Roosnek E, et al. Human NK cells can control CMV infection in the absence of T cells. Blood 2008;112:914–5. [43] Della Chiesa M, Falco M, Podesta M, Locatelli F, Moretta L, Frassoni F, et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood 2012;119:399–410. [44] Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, et al. The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer-cell subsets associated with high levels of HIV-1 viremia. Blood 2009;114:3822–30. [45] Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo X, et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C + natural killer cells with potent function. Blood 2011;119:2665–74. [46] Montaldo E, Del Zotto G, Della Chiesa M, Mingari MC, Moretta A, De Maria A. Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. Cytometry A 2013, http://dx.doi.org/10.1002/cyto.a.22302. [47] Ruggeri L, Aversa F, Martelli MF, Velardi A. Allogeneic hematopoietic transplantation and natural killer cell recognition of missing self. Immunol Rev 2006;214:202–18. [48] Moretta L, Locatelli F, Pende D, Marcenaro E, Mingari MC, Moretta A. Killer Ig-like receptor-mediated control of natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation. Blood 2011;117:764–71. [49] Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, et al. Early human cytomegalovirus replication after transplant is associated with a decreased relapse-risk: evidence for a putative virus-versus-leukemia effect AML patients. Blood 2011;118:1402–12.